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Background: Overexpression of Galectin-3 (Gal-3), a β-galactoside binding protein, has been noted in many tumour types but its functional significance and clinical utility in gastric adenocarcinoma (GAC) are not well known. Methods: We studied 184 GAC patients characterised by histologic grade, sub-phenotypes (diffuse vs intestinal), and ethnicity (Asians vs North Americans). Immunohistochemistry was performed to assess the expression of Gal-3 in human GACs and we correlated it to the clinical outcomes. Cell proliferation, invasion, co-immunoprecipitation and kinase activity assays were done in genetically stable Gal-3 overexpressing GC cell lines and the parental counterparts to delineate the mechanisms of action and activity of inhibitors. Results: Most patients were men, Asian, and had a poorly differentiated GAC. Gal-3 was over-expressed in poorly differentiated (P=0.002) tumours and also in diffuse sub-phenotype (P=0.02). Gal-3 overexpression was associated with shorter overall survival (OS; P=0.026) in all patients. Although, Gal-3 over-expression was not prognostic in the Asian cohort (P=0.337), it was highly prognostic in the North American cohort (P=0.001). In a multivariate analysis, Gal-3 (P=0.001) and N-stage (P=

Programmed death ligand 1 (PD-L1) is a key protein upregulated by tumor cells to suppress immune responses. Tumor-associated macrophages (TAMs) play a major role in this immunosuppression, but the relationship between PD-L1 expression and TAMs remains unclear in gastric adenocarcinoma (GAC). We simultaneously examined expression of PD-L1 and TAMs in GAC. We performed immunohistochemical staining for PD-L1, CD68 (pan-macrophage), and CD163 (M2-like macrophage) in 217 GAC samples using a tissue microarray. Expression of PD-L1 and CD68- and CD163-positive cells was evaluated using the Cytoplasmic V2.0 algorithm in Aperio ImageScope software, and logistic regression analysis was used to compare expression patterns between groups. Thirty-one samples (14%) were positive for PD-L1 expression. The mean (± standard error) rates of infiltration were 6.83 ± 0.38% for CD68-positive cells and 6.16 ± 0.29% for CD163-positive cells. The mean rate of CD163-positive cell infiltration was significantly higher in diffuse GAC than in intestinal GAC (diffuse n = 111, 6.91%; intestinal n = 91, 5.26%; p = 0.006), but the mean rate of CD68-positive cell infiltration was similar between these types (p = 0.38). The mean infiltration rates of CD68- and CD163-positive cells in PD-L1-positive GAC were significantly higher than in PD-L1-negative GAC (CD68 p = 0.0002; CD163 p

Summary Immunological responses in human intestinal allografts are poorly understood and accurate diagnosis of acute cellular rejection remains difficult. Here, human intestinal allografts were analyzed by multi-color quantitative fluorescent immunohistochemical morphometry in order to monitor the clinical course of rejection. Morphometry gave two-dimensional plots based on size and circularity, and identified phenotypes of individual cells infiltrating the allograft by fluorescent staining. Using this method, invariant TCRVα24+ NKT (iNKT) cells were observed in the intestinal allograft during rejection. Because these were not identified in the normal donor intestine before surgery, this finding was considered to be a signature of acute cellular rejection of the intestinal allograft. Infiltrating iNKT cells released IL-4 and IL-5, Th2-related cytokines that antagonize the Th1 responses that induce acute cellular rejection. Histological observation suggested eosinophilic enteritis in the mucosa with elevation of IL-4 and IL-5. In conclusion, iNKT cells were recruited to the intestine; however, because higher levels of IL-4 and IL-5 may contribute to eosinophilic enteritis, timely steroid administration is recommended for allograft injury due to enteritis, as well as acute cellular rejection.

症例は78歳，女性．大腸癌術後2週間目に腹部膨満を主訴として来院．腸閉塞を疑って施行した腹部CTで大腸の壁肥厚および脾彎曲から下行結腸にかけての著明な拡張を認め，中毒性巨大結腸症と診断．さらに大腸内視鏡で偽膜形成を認め，Clostridium difficile（CD）毒素陽性であったため劇症型CD腸炎が原因と判断した．全身状態も安定していたため初期には保存的加療を選択したが，入院後4日目にDICを併発し緊急で結腸全摘術および回腸瘻造設を施行した．術後経過は良好で特に合併症なく術後28日目に退院となった．劇症型CD腸炎は手術を考慮する必要があるが，下痢症状を伴わない場合は早期診断が困難な場合もある．今回は迅速に診断し救命しえた劇症型CD腸炎を経験したため文献的考察を含め報告する．

完全内臓逆位症を伴った胆石症に対する腹腔鏡下胆嚢摘出術を経験した．症例は65歳，男性．心窩部痛を主訴に発症し，胆嚢内には多数の結石を認めた．肝・胆嚢は左側にあり，通常位とは完全に左右対称の鏡面する部位に位置していた．胆道3D-CTでは胆嚢管から胆嚢内への造影剤の流入はないものの，胆道系の走行に変位は認めなかった．手術は臍直下に腹腔鏡用ポート，ワーキングポートは3本で，左中鎖骨線上では肋弓下から7cm足側に離して留置した．胆嚢を厚く覆っていた大網を慎重に剥離したのちcritical viewを露出，確認したうえで胆嚢動脈，胆嚢管をそれぞれクリップ後に切離した．両手を用いるdouble hand法で行ったが，左手での剥離操作を必要とする場面が多かった．経過は順調で術後2日目に退院された．今回，完全内臓逆位での腹腔鏡下胆嚢摘出術を経験したが，右手操作のみならず左手操作にも習熟しておくことが手術を安全に完遂するうえで重要であると思われた．

症例は59歳の男性で，既往に直腸癌，ベーチェット病，ホジキンリンパ腫，上行結腸癌がある．胃癌に対して胃切除術を施行した際に，横行結腸に3 cm大の腫瘤性病変を認めたため合併切除を行った．病理組織学的検査結果は筋線維芽細胞性腫瘍であった．術後7か月目より右季肋部痛が出現し，腹部CTにて肝臓に多発低吸収域が認められた．肝生検の結果，筋線維芽細胞性腫瘍の肝転移と考えられた．肝転移巣の進行抑制を目的に，Mitomycin CとDegradable starch microspheresを用いた肝動注療法を週1回7コース施行したが，術後14か月目に肝不全にて死亡した．

目的: 大腸癌術後症例に対するProbioticsの薬剤効果について検討．対象と方法: 再発，重篤な併存疾患を除く大腸癌術後201例に対してProbiotics服用の意思確認を行い，希望者80名を対象．ザ·ガード（納豆菌，乳酸菌含有）を3カ月間提供し，服用前後でアンケート調査を施行．QOLスコアとしてSF-36, EORTC QLQ-C30および排便機能に関する質問項目を使用．成績: 66名からアンケート回収．内訳は右側結腸癌18例，左側結腸癌23例，直腸癌22例．排便習慣の改善は63.5%，服用継続希望も61.9%と高かった．Probiotics服用後では排便回数，残便感の改善が見られ，QOLに関してもSF-36の社会生活機能，日常役割機能の2項目およびQLQ-C30のGlobal QOL, Constipation, Diarrheaの3項目で改善がみられた．結論: 大腸癌術後ではProbiotics服用により排便習慣の改善，QOLの向上が期待できる.

目的 : 鼠径ヘルニアに対するtension free repairは合併症・再発率とも低いことが報告されているが, 両側同時手術症例の検討は少ない. 今回両側ヘルニアの特徴および同時手術の安全性について検討した. 方法 : 1993年1月～2003年9月に治療された成人鼠径ヘルニア患者899症例 (A群 : 両側153例, B群 : 片側746例) を対象とし, 両群の特徴, 術後合併症, 再発率をretrospectiveに比較検討した. 結果 : 片側を主訴に来院した症例の10%に両側ヘルニアを認めた. ヘルニアのタイプはB群で外鼠径76%, A群で両側内鼠径45%, 両側外鼠径30%, 両側異なるタイプ25%であった. 術後入院期間 (A群 : 3.6日, B群 : 3.2日), 術後合併症 (1.9% vs 1.8%), 再発率 (メッシュ不使用例6.5% vs 3.9%, 使用例は両群とも0%) はいずれも両群に差を認めなかった. 結論 : 鼠径ヘルニアの診察では対側の有無の確認が重要で, 両側同時に手術することは安全である.

症例は78歳, 女性. 心窩部不快と悪心を認め他院受診し, 腹部CT検査にて膵頭部腫瘍疑われ当科受診となった. 主訴は心窩部不快と悪心. 身体所見にて臍右側に境界明瞭で可動性良好な腫瘤を触知した. 腹部超音波検査では膵頭部外側に後方エコーの増強を伴う68×43mm大の境界明瞭な充実性腫瘤を認めた. 腹部CT検査では膵頭部外側に辺縁および内部に不均一な造影効果を伴う径6.5cm大の境界明瞭な充実性腫瘤を認め, MRI検査ではT2強調像で不均一な高信号を示す腫瘤を認めた. 以上の所見より膵漿液性嚢胞腺腫, 十二指腸GISTを想定し手術施行した. 術中所見にて膵頭部に6cm大の弾性軟腫瘤を認めたため, 幽門輪温存膵頭十二指腸切除術施行し, 術後病理組織学的検索で漿液性嚢胞腺腫と診断された. 膵外へ発育し, 可動性のある腫瘤として認められた漿液性嚢胞腺腫は非常に珍しいと考えられたので文献的考察を加えて報告する.

症例は81歳, 男性. 主訴は黄疸, 褐色尿. 腹部超音波検査, 造影CT検査で膵頭部に径6cm大の多房性嚢胞様病変を認めた. 十二指腸への直接浸潤, 総胆管の拡張も疑われたが, 主膵管に拡張を認めなかった. 上部消化管内視鏡検査では十二指腸球部内腔に腫瘍が露出し, 多量の粘液を認めた. PTCDでは下部胆管に先細り状の狭窄を認め, 胆汁細胞診で腺癌と診断された. 以上の所見より, 膵粘液癌, 分枝型膵管内乳頭状粘液性腫瘍 (以下, 分枝型IPMT) 由来の浸潤癌などを想定し手術施行した. 術後病理組織学的検査で粘液結節の中に腺癌の胞巣を認め, 膵粘液癌と診断された. しかし, 術前検査では膵頭部から十二指腸に浸潤する造影効果の乏しい多房性腫瘍を認め, 腫瘍部の生検で多量の粘液と高円柱状, 粘液上皮様の細胞を認めており, 粘液癌と分枝型IPMT由来の浸潤癌の鑑別は困難であった.

Purpose: Human invariant natural killer T (NKT) cells are novel, distinct lymphocyte populations with a restricted T-cell receptor repertoire (Vα24-Vβ11). They play a pivotal role in immunoregulation and in antitumor activities. This study focused on Vα24+ NKT cells in colorectal carcinomas and their clinicopathologic significance.Experimental Design: Vα24+ NKT-cell infiltration immunohistochemistry was studied in a total of 103 colorectal carcinoma cases. The degree of NKT-cell infiltration in tumors was evaluated as low (Results: A small number of Vα24+ NKT cells were found in the normal colorectal mucosa (2.6 ± 3.7 cells/5 HPF); however, their number increased remarkably in colorectal carcinomas (15.2 ± 16.3 cells/5 HPF; P = 0.0003) and a majority showed phenotype of activation. Higher NKT-cell infiltration was more frequent in women than in men (P = 0.034) and correlated with fewer lymph node metastases (P = 0.042). Patients with high NKT-cell infiltration showed higher overall (P = 0.018) as well as disease-free (P = 0.0006) survival rates. Intratumor NKT-cell infiltration was an independent prognostic factor for the overall (P = 0.033) and disease-free (P = 0.0064) survival rates.Conclusions: Increased infiltration of Vα24+ NKT cells was observed in colorectal carcinomas. Higher Vα24+ NKT-cell infiltration in colorectal carcinomas was an independent prognostic factor for favorable prognosis.

Objectives: Immature microvessels, which are not covered by pericytes, are irregular and leaky. We hypothesized that tumor cells can penetrate immature microvessels more easily than mature microvessels. In this study, we investigated the maturation of angiogenesis by the immunohistochemical staining of colorectal cancer specimens and determined the correlation between the microvessel count or the maturity of microvessels and clinicopathological variables. Methods: Ninety-two surgical specimens from our department were used. Double immunostaining of endothelial cells with anti-CD34 antibody and pericytes with anti-α-smooth muscle actin antibody was performed. The microvessel density (MVD) and microvessel pericyte coverage index (MPI) as an index of microvessel maturation were evaluated. Results: The MVD showed a significant positive correlation with tumor size, depth of invasion and Dukes’ stage. The MPI showed a significant positive correlation with the histological differentiation of the tumor tissues and distant metastasis at the time of operation. The high MVD group (≧26.0, n = 50) tended to have a poorer prognosis than the low MVD group (Conclusions: These findings demonstrate that immature neovascularization was observed in poorly differentiated tumors and was correlated with metastasis, resulting in a poorer prognosis. Taken together, not only microvessel density but also vascular maturation were crucial factors for colorectal cancer patients.

大腸全摘術を行った家族性大腸腺腫症 (FAP) 患者の経過観察で注意する点は, 十二指腸ポリープ, 特に発生率の高いVater乳頭部周辺のポリープの癌化である. 癌化に対して膵頭十二指腸切除を余儀なくされることもあるため, 予防的処置が必要とされる. 今回, 我々はFAPの大腸全摘術後, 残存する十二指腸ポリポーシスに対して膵温存十二指腸切除術 (PPTD) を施行した1例を経験した. 症例は40歳の男性で, FAPおよび併発した直腸癌に対して大腸全摘術を行った. 約4か月後に明らかとなった肝転移および密生する十二指腸ポリポーシス (管状腺腫) に対し, 肝右葉切除およびPPTD (B-I再建) を施行した. 術後, 縫合不全, 膵液漏, 胆汁漏などの合併症はなく, 食事摂取も良好で通常の日常生活に復帰できた. 根治性や機能予後につき長期の観察と評価が必要だが, PPTDはFAP の十二指腸ポリポーシスに対して有効な治療法であると考えられた.

Vascular endothelial growth factor (VEGF) plays a central role in tumour angiogenesis. In a mouse intramuscular tumour model using VEGF-transfected HT1080 human fibrosarcoma, we investigated the morphological features and patterns of remodelling in size-matched tumours. Compared with the control tumours (C group), the VEGF-transfected tumours (V group) showed vigorous neovascularization with larger vessels. Fenestrations and disruptions of endothelia were specific to the V group. Three types of vascular remodelling, i.e. sprouting, luminal division and intussusceptive microvascular growth, were present in both groups. Morphometric analyses revealed that mural cell coverage of the endothelial cells was significantly smaller in the V group compared with that in the C group (V group, 28.2 +/- 18.6%; C group, 41.6 +/- 21.1%; P < 0.0001). To determine the prevalence of remodelling patterns, the occurrences of abluminal and luminal processes on endothelial cell surfaces were quantified. Abluminal processes are defined as cytoplasmic protrusions of the abluminal membrane of endothelial cells, which can vary from tiny spurs to solid sprouts of the cell. On the other hand, luminal processes are defined as intraluminal protrusions of the endothelial cell membrane, including various membranous changes from filiform processes to rather thick cytoplasmic bulges. An abluminal process is thought to represent an initial morphological change in sprouting type angiogenesis, and a luminal process to be a sign of implementation of luminal division. The frequency of abluminal processes was significantly higher in the V group than in the C group (V group, 0.243 +/- 0.138/microm; C group, 0.114 +/- 0.101/microm; P < 0.0001). In contrast, the number of luminal processes on the endothelial cells per micrometre was statistically comparable between the groups (V group, 0.285 +/- 0.252/microm; C group, 0.309 +/- 0.236/microm, P = 0.381). These results indicate that sprouting is the main mode of VEGF-induced tumour angiogenesis.

症例は78歳女性.主訴は右季肋部痛で,画像検査で肝門部に手拳大の腫瘍を認め,肝への直接浸潤を伴った胆嚢癌と術前診断された.血液検査では白血球が高値を示した.肝部分切除を伴う胆嚢摘出術が施行され,扁平上皮癌と病理診断された.術後9カ月目に肝転移をきたしたのと同時に白血球が再上昇したため, G-CSF産生腫瘍を疑い血中G-CSF値測定,および抗G-CSF抗体による腫瘍組織の免疫染色を行った.血中G-CSF値は正常の約3倍と高値で,かつ腫瘍細胞の細胞質に陽性所見を認めたことからG-CSF産生胆嚢癌と診断した.経過中白血球数, G-CSF値は病状進行とともに上昇した.追加した化学療法が奏効せず術後12カ月で死亡した.胆嚢G-CSF産生扁平上皮癌は稀であり,文献的考察を加え報告した.

症例は31歳の男性で, 平成9年頃からアルコール性膵炎の加療歴があり, 腹部CT検査では膵仮性嚢胞が指摘されていた. 平成12年2月3日に左上腹部痛のため入院. 腹部CT検査では, 膵尾部に直径約5cmの膵仮性嚢胞を認め, 嚢胞内脾門部寄りに造影効果のある径5mm大の腫瘤を認めた. 保存的治療により軽快したが, 3か月後に腹部CT検査を行ったところ, 膵仮性嚢胞の増大と嚢胞内に突出する脾仮性動脈瘤が疑われ, さらに嚢胞内への出血も疑われた. 5日後の腹部CT検査で動脈瘤の増大を認めたため, 血管撮影を行い, 脾仮性動脈瘤を確認した後, 同部の血管塞栓術を行った. 2週間後, 待期的に膵仮性嚢胞の根治術として動脈瘤を含めた膵体尾脾合併切除術を行い良好な結果を得ている.

Functional genetic variants of DNA repair genes may alter the host DNA repair capacity, and thus influence efficiency of therapies. We genotyped eight potentially functional single nucleotide polymorphisms (SNPs) in genes (i.e. ERCC1, XPA, XPC, XPD and XPG) involved in the nucleotide excision repair (NER) pathway in 496 Japanese gastric cancer patients, and assessed overall survival and recurrence-free survival. The combined effects of risk genotypes of these eight SNPs in Japanese patients were further replicated in 356 North-American gastric cancer patients. In Japanese patients, we found that the XPC rs2228000 TT genotype was associated with shorter overall survival [hazards ratio (HR) = 1.75, 95% confidence interval (95% CI) = 1.07-2.86] and recurrence-free survival (HR = 2.17, 95% CI = 1.19-3.95), compared with CC/CT genotypes, and the XPG rs17655 CC genotype was associated with shorter overall survival (HR = 1.60, 95% CI = 1.08-2.36), compared with GG/CG genotypes. The number of observed risk genotypes in the combined analysis was associated with shorter overall survival and recurrence-free survival in a dose-response manner (P(trend) = 0.006 and P(trend) < 0.000) in Japanese patients; specifically, compared with those with ≤1 risk genotypes, those with ≥2 risk genotypes showed markedly shorter overall survival (HR = 1.79, 95% CI = 1.18-2.70) and recurrence-free survival (HR = 2.80, 95% CI = 1.66-4.73). The association between ≥2 risk genotypes and shorter overall survival was not significant (HR = 1.26, 95% CI = 0.82-1.94) in North-American patients, but the trends were similar in these two groups of patients. These data show that functional SNPs in NER core genes may impact survival in Japanese gastric cancer patients.

BACKGROUND It still is unclear when angiogenic potential, which is believed to be a prerequisite for tumor development, is acquired. The current study was designed 1) to clarify when the phenotypic change of angiogenicity occurs during the development of colon carcinoma and 2) to investigate the possible roles of vascular endothelial growth factor (VEGF) and p53 in angiogenesis. METHODS Colon carcinomas were classified according to the following criteria: m carcinomas were tumors in which carcinoma cells were observed within the mucosa (excluding adenomas with severe atypia) according to the World Health Organization criteria. sm carcinomas were defined by invasion into the submucosa but not into the muscularis propria. Using 27 adenomas, 26 m carcinomas, and 20 sm carcinomas, VEGF expression was analyzed with reverse transcriptase-polymerase chain reaction and immunohistochemistry. Microvessel density, VEGF, and p53 status were evaluated by immunohistochemistry. RESULTS Neither VEGF mRNA nor VEGF protein was detected in any of the mild-to-moderate dysplastic adenomas, whereas 16 of 26 m carcinomas (62%) and all sm carcinomas exhibited VEGF protein. The microvessel density in adenomas, m carcinomas, and sm carcinomas was 3 ± 0.55, 6.1 ± 1.12, and 12 ± 1.35 (0.739 mm2 per field), respectively. In m carcinomas, positive VEGF expression was coincident with the expression of p53, and stainability for both VEGF and p53 was similar with regard to spatial distribution in tumor tissues. In m and sm carcinomas, there was a statistically significant correlation between the intensity of VEGF expression and microvessel density. CONCLUSIONS The results of the current study demonstrated that angiogenesis develops in association with tumor progression from adenoma to noninvasive colorectal carcinoma, at least in part due to VEGF, and suggested that VEGF in m carcinomas is induced by mutant p53, although alternative mechanisms of VEGF up-regulation may exist in sm carcinomas. Cancer 2000;88:1820–7. © 2000 American Cancer Society.

Vascular endothelial growth factor (VEGF) may affect the phenotype of cancer cells, such as growth velocity and metastatic potential, due to its probable multifunctional property including a mitogenic activity for vascular endothelial cells. The present study was designed to investigate the association of VEGF mRNA expression with progression and metastasis of human colorectal cancer. The level of VEGF mRNA expression was quantified by Northern blot hybridization in tumorous and non-tumorous tissues obtained from 60 primary colorectal cancer patients. The ratio of the former to the latter was defined as the VEGF T/N ratio, and the prognostic significance of this ratio, following surgery, in addition to the relationship to progression and metastatic potential, was evaluated. The value of the VEGF T/N ratio was significantly correlated with the depth of tumour infiltration (P=0.046), the incidence of liver metastasis (P < 0.0001) and lymph node metastasis (P=0.036). Patient prognosis was estimated by the Kaplan-Meier method and the log-rank test. When the VEGF T/N ratio was higher than 4.8 for which the chi2 value of the log-rank test was maximal, the tumour was defined as showing overexpression of VEGF mRNA. Patients with overexpression of VEGF mRNA demonstrated poorer survival than patients without overexpression of VEGF mRNA (P < 0.001). The overall estimated hazard ratio for death in patients with overexpression of VEGF mRNA was 1.94 according to a multivariate analysis (P=0.005). Thus, VEGF is associated with the progression, invasion and metastasis of colorectal cancer, and overexpression of VEGF mRNA in the primary tumour is assumed to be closely correlated with poor prognosis in colorectal cancer patients. Moreover, the VEGF T/N ratio may be used as an independent prognostic marker in colorectal cancer patients. Images Figure 1

A highly sensitive system was previously developed by us to detect the presence of colorectal carcinoma cells in blood in the form of cytokeratin 20 (CK20) mRNA. In the present study, we used an improved version of this system to analyse the peripheral blood of 28 patients with colorectal carcinoma, five patients with non-cancerous intestinal diseases and six normal controls for the presence or absence of CK20 mRNA and to investigate the relationship between the mRNA results and prognosis. All eight patients with recurrence were positive for CK20 mRNA, as were four patients in the Dukes' C stage with either distant metastasis or dissemination. Five of the nine patients in the Dukes' C stage with neither distant metastasis nor dissemination were positive, and three of these developed recurrence within 11 months after the analysis. Only one of the seven patients in the Dukes' A or B stage was positive, and none showed recurrence during the 1-19 months of observation. None of the five patients without carcinomas or of the six normal controls was positive. Although the follow-up period is limited and the recurrences were all local at present, these results suggest that the presence of CK20 mRNA in circulation may be a useful indicator for the screening of advanced colorectal carcinoma patients with a high risk of recurrence. Images Figure 1 Figure 2

Although development of human anti-murine immunoglobulin antibody (HAMA) is often seen in patients receiving murine antibodies, the variety of methods used for detecting HAMA makes it difficult to compare directly the HAMA responses measured by different assays. In the present study, several parameters of the HAMA response to two murine monoclonal antibodies were evaluated. The anti-sialosyl Tn antibody MLS102 and anti-CA125 antibody 145-9, which were labeled with 111In, were injected intravenously into 17 colorectal cancer patients and 11 ovarian cancer patients for immunoscintigraphy, respectively. HAMA was measured by enzyme-linked immunosorbent assay. There was no difference in baseline HAMA levels before antibody injection between the two groups. HAMA developed more frequently in ovarian cancer patients receiving the 145-9 antibody than in colorectal cancer patients receiving the MLS102 antibody (9/11 vs. 6/17, P < 0.05). No significant difference was observed in maximal HAMA levels between the two groups of patients. However, time to reach the maximal levels was delayed and the duration of the response seemed longer in ovarian cancer patients. Among 11 patients receiving the 145-9 antibody three patients became positive for HAMA more than 2 months after antibody injection and the other two had HAMA activity in their sera for more than 17 months. HAMA response was different between the two antibodies, and late onset or long duration of HAMA response against the 145-9 antibody suggests the importance of HAMA measurement in patients who receive a second injection of murine antibodies even after a long interval.

Immunological responses in human intestinal allografts are poorly understood and accurate diagnosis of acute cellular rejection remains difficult. Here, human intestinal allografts were analyzed by multi-color quantitative fluorescent immunohistochemical morphometry in order to monitor the clinical course of rejection. Morphometry gave two-dimensional plots based on size and circularity, and identified phenotypes of individual cells infiltrating the allograft by fluorescent staining. Using this method, invariant TCRVα24(+) NKT (iNKT) cells were observed in the intestinal allograft during rejection. Because these were not identified in the normal donor intestine before surgery, this finding was considered to be a signature of acute cellular rejection of the intestinal allograft. Infiltrating iNKT cells released IL-4 and IL-5, Th2-related cytokines that antagonize the Th1 responses that induce acute cellular rejection. Histological observation suggested eosinophilic enteritis in the mucosa with elevation of IL-4 and IL-5. In conclusion, iNKT cells were recruited to the intestine; however, because higher levels of IL-4 and IL-5 may contribute to eosinophilic enteritis, timely steroid administration is recommended for allograft injury due to enteritis, as well as acute cellular rejection.

Objective. Mesorectal excision corresponding to the location of a tumor, termed tumor-specific mesorectal excision (TSME), is commonly performed for resection of upper rectal cancer. We devised a new laparoscopic procedure for sufficient TSME with rectal transection followed by mesorectal excision.Operative Technique. After mobilization of the sigmoid colon and ligation of inferior mesenteric vessels, we dissected the mesorectum along the layer of the planned total mesorectal excision. The rectal wall was carefully separated from the mesorectum at the appropriate anal side from the tumor. After the rectum was isolated and transected using an endoscopic linear stapler, the rectal stump drew immediately toward the anal side, enabling the mesorectum to be identified clearly. In this way, sufficient TSME can be performed easily and accurately. This technique has been successfully conducted on 19 patients.Conclusion. This laparoscopic technique is a feasible and reliable procedure for achieving sufficient TSME.

教室で過去25年間に経験した直腸悪性黒色腫3例を報告した.これは全直腸悪性腫瘍の0.5%(3/538)にあたる.2例が女性(72歳,56歳),1例が男性(80歳)であり,全例に腹会陰式直腸切断術を施行した.術前MRI検査を行った最近の1例は,癌腫と異なりT1強調画像で高信号,T2強調画像で低信号を示し,術前診断が可能であった.この症例はDAV(DTIC, ACNU, Vincristine)療法の併用で1年6か月生存中であるが,他の2例はそれぞれ6か月,2年2か月で原病死した.本症は予後不良で,安易な生検は転移を促進するため禁忌といわれ,MRIを併用した術前診断は極めて有用と思われた.治療法として手術術式や,さらに近年脚光を浴びているサイトカイン遺伝子導入療法についても文献的考察を含め報告した.

Background Intestinal fibrosis leading to severe bowel dysmobility or obstruction is a troublesome adverse effect of abdominal or pelvic radiation therapy. We have recently reported that all-trans-retinoic acid (ATRA) prevents radiation- or bleomycin-induced lung fibrosis. Here, we examined the impact of ATRA on the mouse model of radiation-induced intestinal fibrosis. Materials and methods We evaluated the histology of late radiation fibrosis in surgical samples. We then performed histological examinations and quantitative measurements of mRNA of interleukin-6 and transforming growth factor-β1 in intestinal tissues of irradiated mice with or without intraperitoneal administration of ATRA and investigated the effect of ATRA on the transdifferentiation and the production of collagen of irradiated human intestinal fibroblasts. Results Human samples of late radiation enteritis showed thickened submucosa and serosa, consistent with mouse model. Administration of ATRA attenuated irradiation-induced intestinal fibrosis and reduced mRNA of interleukin-6 and transforming growth factor-β1. In vitro studies disclosed that ATRA suppressed the transdifferentiation of irradiated intestinal fibroblasts and diminished the production of collagen from the cells. Conclusions Our findings indicate that ATRA ameliorates irradiation-induced intestinal fibrosis. ATRA could be a novel approach in the treatment of fibrosis associated with chronic radiation enteritis.

Background: Appropriate partial mesorectal excision (PME) is extremely important for prevention of local recurrence even in upper rectal cancer. However, it is not always easy to conduct PME in the narrow pelvic cavity. We devised a new surgical technique that involves a rectal transection followed by PME. Methods: After rectal mobilization in the layer targeted for total mesorectal excision, only the rectal wall was bluntly dissected at an appropriate distance from the tumor. Initial transection of the rectum allows drawing the rectum toward the anal side so that the mesorectum can be confirmed with a good visual field. Excision of the mesorectum was easy, and it could be resected in a short time. Results: This technique was conducted on seven patients with upper rectal cancer and on four patients with rectosigmoid cancer. Separation of the rectal wall was comparatively easy, and we had no incidence of wall injury. The average distance from the rectal stump to the distal mesorectum in the freshly resected specimen was 15 mm, indicating satisfactory PME. Conclusions:This easily performed method is a promising procedure for achieving sufficient PME in upper rectal cancer.

The concepts of vasculogenic mimicry and mosaic vessels have been proposed as novel modes of tumour neovascularisation. However, the presence and significance of these types of neovascularisation remain unclear.ECV304 human bladder carcinoma cells were used to determine how tumour cells take part in tumour neovascularisation.Subcutaneous ECV304 xenografts in mice showed various vessel types, including angiogenic vessels, tumour cell-related vessels and extracellular matrix networks. A tracer experiment demonstrated perfusion of beads in these structures. ECV304 cells, cultured on collagen I gels, formed tube networks with expressions of several endothelial-related markers. In coculture models of ECV304 cells and human umbilical vein endothelial cells, the two cells collaborated to form sprouts or networks.ECV304 cells possess an endothelial character which confers the ability to mimic and collaborate with vascular endothelial cells and facilitates the acquisition of tumour microcirculation.

Vascular endothelial growth factor (VEGF) plays a central role in tumour angiogenesis. In a mouse intramuscular tumour model using VEGF-transfected HT1080 human fibrosarcoma, we investigated the morphological features and patterns of remodelling in size-matched tumours. Compared with the control tumours (C group), the VEGF-transfected tumours (V group) showed vigorous neovascularization with larger vessels. Fenestrations and disruptions of endothelia were specific to the V group. Three types of vascular remodelling, i.e. sprouting, luminal division and intussusceptive microvascular growth, were present in both groups. Morphometric analyses revealed that mural cell coverage of the endothelial cells was significantly smaller in the V group compared with that in the C group (V group, 28.2 +/- 18.6%; C group, 41.6 +/- 21.1%; P0.0001). To determine the prevalence of remodelling patterns, the occurrences of abluminal and luminal processes on endothelial cell surfaces were quantified. Abluminal processes are defined as cytoplasmic protrusions of the abluminal membrane of endothelial cells, which can vary from tiny spurs to solid sprouts of the cell. On the other hand, luminal processes are defined as intraluminal protrusions of the endothelial cell membrane, including various membranous changes from filiform processes to rather thick cytoplasmic bulges. An abluminal process is thought to represent an initial morphological change in sprouting type angiogenesis, and a luminal process to be a sign of implementation of luminal division. The frequency of abluminal processes was significantly higher in the V group than in the C group (V group, 0.243 +/- 0.138/microm; C group, 0.114 +/- 0.101/microm; P0.0001). In contrast, the number of luminal processes on the endothelial cells per micrometre was statistically comparable between the groups (V group, 0.285 +/- 0.252/microm; C group, 0.309 +/- 0.236/microm, P = 0.381). These results indicate that sprouting is the main mode of VEGF-induced tumour angiogenesis.

Skeletal muscle is an uncommon site of hematogenous metastasis of gastric carcinoma. We report here a rare case of gastric carcinoma with multiple intramuscular metastases. Our patient had advanced gastric carcinoma and complained of left gluteal induration with tenderness. Because magnetic resonance imaging (MRI) revealed that the gluteal tumor showed iso-signal intensity on T1-weighted images and high signal intensity on T2-weighted images, with reticulated texture around the tumor, and the patient had advanced gastric carcinoma, we speculated that the tumor was an intramuscular metastatic tumor from primary gastric carcinoma. There were also multiple intramuscular metastatic lesions in both gluteal muscles on the MRI findings that were not detected by physical examination. Therefore, the patient underwent total gastrectomy with combined resection of spleen, with subsequent chemotherapy. Three months after the operation, we excised the gluteal tumor to alleviate the gluteal pain. Histological examinations confirmed that the gluteal tumor was a metastasis from primary gastric carcinoma.

BACKGROUND Human macrophage metalloelastase (HME), also referred as matrix metalloproteinase 12, has been shown to convert plasminogen into angiostatin, an essential inhibitor of tumor angiogenesis. The current study was designed to investigate the association of HME mRNA expression with disease progression of in patients with colorectal carcinoma. METHODS The expression of HME mRNA was quantified by Northern blot analysis in tumorous (T) and nontumorous (N) tissues obtained from 54 patients with primary colorectal carcinoma, and the ratio of these two tissue types was defined as the HME T/N ratio. The prognostic significance of this ratio after surgery, along with its correlation with disease progression and metastatic potential, was evaluated. The tissues also were subjected to in situ hybridization analysis for HME. The microvessel count after immunohistochemical staining of factor VIII was used to assess angiogenesis. RESULTS The HME T/N ratio showed an inverse correlation with the depth of the intestinal wall invasion, the lymphatic invasion, and the vascular invasion. The patients with overexpression of HME mRNA (HME T/N ratio > 1.191) significantly demonstrated better survival compared with those patients who did not show overexpression of HME mRNA. In situ hybridization identified the colorectal carcinoma cells as mainly responsible for the signal shown in Northern blot analysis. A considerable but not statistically significant lower microvessel density (MVD) was observed in the patients with HME overexpression. CONCLUSIONS These findings demonstrate that the HME gene plays an important role in the inhibition of tumor progression in patients with colorectal carcinoma and that its overexpression is correlated closely with a better prognosis. Cancer 2001;91:1277–83. © 2001 American Cancer Society.

We developed a novel blood glucose control system, using a model predictive method, to achieve optimal control of the blood glucose level in severely diabetic or pancreatectomized patients. This system is designed to predict glucose level changes in advance, considering delayed response time and the administered doses of insulin. This method is also designed to calculate the most appropriate insulin infusion rate by considering differences in individual response to insulin. In this study, we compared our system with a conventional proportional and differential controller (PD controller) to determine whether the new system could regulate the glucose level efficiently in pancreatectomized dogs. The model predictive control method resulted in a significant reduction of mean insulin infusion rate compared with the conventional PD controller (0.71 mU/kg per min vs. 1.81 mU/kg per min, p = 0.0005), when the glucose level in both methods reached the planned target level (100 mg/dl). The new system also tended to have a reduced mean glucose infusion rate for compensating for overshooting of the glucose level compared with the PD controller (0.7 mg/kg per min vs. 1.1 mg/kg per min, p = 0.16). These results indicate that the new system should be a useful tool for regulating the glucose level in severely diabetic patients.

Recently, several retrospective studies have shown an inverse association between appendectomy and development of ulcerative colitis. We describe a 21-year-old man with distal ulcerative colitis and appendiceal involvement. The patient passed bloody stools continually during the 3 years before admission. Macroscopic and microscopic findings showed chronic moderate inflammation of the appendix and rectum. The ratio of CD4 to CD8 lymphocytes isolated from rectal and appendiceal mucosa was increased (4.3 and 3.8, respectively) compared with controls (n = 11; 1.0 in the rectum and 1.4 in the appendix). Clinical symptoms and colonoscopic and microscopic findings improved significantly after appendectomy. In addition, the amount of interferon gamma secreted from rectal lymphocytes was reduced to 89 pg/mL after surgery (before appendectomy, 254 pg/mL). However, interleukin 4 production was below detectable levels both before and after appendectomy. These findings suggest that appendectomy resulted in altered T-helper (Th)1/Th2 balance in this patient. In the 3 years since surgery, the patient has been in good condition without recurrence of symptoms. This is the first report demonstrating therapeutic benefit of appendectomy in a patient with ulcerative colitis and potential mechanistic relationship.